1. Field of the Invention
The invention relates to ophthalmic drug delivery systems for reducing the incidence or severity of, or for preventing, cataracts.
2. Description of Related Art
The idea of using estrogen to protect lenses of the eye from cataract formation was published at least as early as 1997, in Hales, A., et al., “Estrogen Protects Lenses against Cataract Induced by Transforming Growth Factor-β (TGFβ),” J. Exp. Med., The Rockefeller University Press, Vol. 185, pp. 273-280, January 1997. There have been many previous attempts to prepare a delivery system to introduce estrogen into the eye to attempt to reduce cataract formation. Prior attempts have been plagued with problems including but not limited to poor shelf stability; inadequate microbiostatic characteristics; inadequate delivery and bioavailability; and formulation difficulties due to the hydrophobic character of estrogen compounds and the particularly sensitive nature of eye tissues and eye fluid tolerances.
The high risk of cataracts in women is believed to be due to the sharp decline in estrogen levels that occur after menopause, although men experience cataracts also. Exposure to estrogen has been determined in human and animal studies to be protective by reducing the risk of cataracts. Although clinical and preclinical studies suggest that systemically administered estrogen therapy may reduce the risk of cataracts, many women are concerned about taking systemic estrogen treatments for fear of increasing other risks, especially breast cancer. Moreover, men who wish to avoid cataracts generally find the idea of systemic estrogen unacceptable. Ophthalmic administration (conjunctival sac instillation) of estrogen would eliminate the disadvantages of systemic administration including those mentioned above and also avoid the unwanted hepatic first-pass effect.
The concept of preparing an ophthalmic drug delivery system for estrogen is thus straightforward in itself, although it has heretofore posed an implementation challenge. In situ gel forming pharmaceuticals for eye instillation face an inherent paradox during their design phases. Engineering a liquid that will have low enough viscosity to make a good dropwise eye product that can still quickly form a gel in the eye is a conundrum to begin with, and then making such a quick-change composition shelf-stable, sterile and adequately antibacterial adds an additional challenge, not to mention identifying an overall medium compatible with the active agent to be delivered. For example, eye-compatible gel forming agents are most beneficially chosen from among amino acid or saccharide polymers, to avoid toxicity, and yet these constituents are themselves intrinsically likely to foster unacceptable growth of unwanted bacteria or other microbes in the eye. The chemical reactivities of a particular active agent require specialized engineering of the carrier to assure the gel-forming carrier is completely inert to the drug. The present invention overcomes all these challenges in presenting a new and surprisingly useful formula for delivering at least one estrogen topically to the eye, to treat cataracts already formed or forming or to reduce the incidence of cataract formation when topical treatment is provided to a healthy human eye. In particular, ophthalmic delivery of estrogen has to overcome several difficulties such as wastage of drug by rapid naso-lachrymal drainage, increased tear turnover upon instillation of the formulation and inherent physicochemical properties of the drug molecules, and particularly the troublesome hydrophobicity of estrogen as well as the extremely sensitive nature overall of the eye. As a paramount consideration, not only must the ophthalmic composition be safe and effective in the eye, but it must not create even the slightest discomfort or blurred vision or any other feature that the patient might find unacceptable, both to avoid eye damage and to maximize patient compliance.